DESCRIPTION: Varicella zoster virus (VZV) infection is a major cause of morbidity in children and older adults and may be life threatening in the immunocompromised host. Over 90% of the adult population is seropositive for VZV and are thus candidates for zoster and its attendant frequent, serious complication, post-herpetic neuralgia. At present, we have little hard information on the pathogenesis and lifestyle of this important human virus. However, thanks to very recent advances in VZV molecular genetic technology and in the SCID/Hu animal model, we are, for the first time, in a position to address fundamental questions about VZV pathogenesis and disease. A consortium has been organized to deal with these issues, since a multidisciplinary approach is essential. Specifically, we have chosen candidates from two groups of VZV polypeptides for our study: gene regulatory proteins and viral enzymes. Based on our own studies and those in herpes simplex virus, we expect that these VZV proteins will largely be dispensable for growth in cell culture, but important for pathogenesis in the host. The aims of the proposal include construction both of vectors expressing VZV proteins, and of viral null mutants that fail to express a particular viral protein. Fundamental properties of two of these proteins (the major regulatory protein, IE62 and the ORF47 protein kinase) will be examined in detail as they relate to behavior in viral growth and pathogenesis. The properties of the viral null mutants will be assessed in the context of pathogenesis and latency in the SCID-hu mouse model. The outcome of the study will be a definition of viral factors important in VZV pathogenesis, leading to a basis for development of logical, novel, preventive therapies for VZV disease.